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首页> 外文学位 >The role of ER quality control and protein misfolding in retinal degeneration caused by a mutation in rhodopsin.
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The role of ER quality control and protein misfolding in retinal degeneration caused by a mutation in rhodopsin.

机译：ER质量控制和蛋白错误折叠在视紫红质突变引起的视网膜变性中的作用。

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摘要

Retinitis Pigmentosa (RP) is a group of inherited, degenerative diseases of the retina affecting about 1.5 million people worldwide. There is no existing cure for these diseases, and the modes of toxicity are poorly understood. The most common cause of autosomal dominant RP (ADRP) can be linked to mutations in the gene encoding rhodopsin, a G-protein coupled receptor that mediates phototransduction in the outer segments of rod cells in the retina. A majority of ADRP-linked rhodopsin mutants fail to mature beyond the endoplasmic reticulum, suggestive of a defect in protein folding. In this thesis, the misfolding behavior of a common ADRP-linked rhodopsin mutant, P23H, has been investigated. It was found that the P23H mutation endows the rhodopsin molecule with a high propensity to form oligomers. Whole-cell assays based on fluorescence resonance energy transfer (FRET) were developed to study P23H aggregation. It was found that even at the lowest levels of expression, there was near-maximal FRET in P23H, suggesting that protein aggregation was a gain of function for this mutant. The remainder of the thesis was devoted to understanding how P23H oligomerization may contribute to cellular toxicity. P23H aggregation was found to be highly specific, excluding possibilites of co-aggregation with general cellular factors. However, P23H aggregates had the capacity to impair the ubiquitin-proteasome pathway, suggesting one direct mode of toxicity. In another set of experiments, it was observed that in cells co-expressing P23H and rhodopsin, the folding of rhodopsin was antagonized by P23H. Upon further investigation, it was discovered that an interaction between P23H and rhodopsin was responsible for this effect, consequently targeting rhodopsin for degradation by the ubiquitin-proteasome pathway. These data suggest that in rod cells, P23H possibly mediates its toxic effect by preventing transport of rhodopsin to the outer segments. In sum, these observations, for the first time, have linked RP to the broad class of neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. The results of this investigation provide a clearer understanding of the cellular defects associated with this disease condition, and will aid in the treatment and possibly in a cure for rhodopsin-linked RP.
机译：色素性视网膜炎（RP）是一组遗传性视网膜退化性疾病，全世界约有150万人受其感染。目前尚无治疗这些疾病的方法，并且对毒性的方式了解甚少。常染色体显性RP（ADRP）的最常见原因可能与编码视紫红质的基因突变有关，视紫红质是一种G蛋白偶联受体，可在视网膜杆状细胞的外部片段中介导光转导。大多数ADRP连接的视紫红质突变体无法成熟到内质网以外，这提示蛋白质折叠存在缺陷。本文研究了常见的ADRP连接的视紫红质突变体P23H的错误折叠行为。发现P23H突变赋予视紫红质分子形成寡聚体的高倾向。开发了基于荧光共振能量转移（FRET）的全细胞检测技术来研究P23H聚集。发现即使在最低的表达水平下，P23H中的FRET也接近最大，表明蛋白质聚集是该突变体功能的获得。本文的其余部分致力于了解P23H寡聚化可能如何导致细胞毒性。发现P23H聚集是高度特异性的，不包括与一般细胞因子共同聚集的可能性。然而，P23H聚集体有能力破坏泛素-蛋白酶体途径，表明一种直接的毒性模式。在另一组实验中，观察到在共表达P23H和视紫红质的细胞中，视紫红质的折叠被P23H拮抗。进一步研究发现，P23H和视紫红质之间的相互作用是造成这种效应的原因，因此将视紫红质靶向通过泛素-蛋白酶体途径降解。这些数据表明，在杆状细胞中，P23H可能通过阻止视紫红质转运到外部片段来介导其毒性作用。总之，这些发现首次将RP与广泛的神经退行性疾病（例如阿尔茨海默氏病和帕金森氏病）联系起来。这项研究的结果使人们更加清楚地了解了与这种疾病状况相关的细胞缺陷，并将有助于视紫红质联结的RP的治疗，甚至可能有助于治愈。

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  • 作者

    Rajan, Rahul Sunder.;

  • 作者单位

    Stanford University.;

  • 授予单位 Stanford University.;
  • 学科 Biology Cell.; Biophysics General.; Chemistry Biochemistry.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 133 p.
  • 总页数 133
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;生物物理学;生物化学;病理学;
  • 关键词

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